NO is an environmental pollutant produced as a byproduct of combustion. At high concentrations (generally at or above 1000 ppm), NO is toxic. NO also is a naturally occurring gas that is produced by the endothelium tissue of the respiratory system. In the 1980's, it was discovered by researchers that the endothelium tissue of the human body produced NO, and that NO is an endogenous vasodilator, namely, an agent that widens the internal diameter of blood vessels.
With this discovery, numerous researchers have investigated the use of low concentrations of inhaled NO to treat various pulmonary diseases in human patients. See Higenbottam et al., Am. Rev. Resp. Dis. Suppl. 137:107, 1988. It was determined, for example, that PPH can be treated by inhalation of low concentrations of NO. With respect to pulmonary hypertension, inhaled NO has been found to decrease pulmonary artery pressure (PAP) as well as pulmonary vascular resistance (PVR).
Prior to the advent of NO inhalation therapy, pulmonary hypertension was treated by the administration of drugs known as systemic vasodilators. These drugs, such as prostacyclin, nitroprusside, hydroalazine, and calcium channel blockers suffered from the limitation that the drugs, by their nature, produced systemic effects. For example, the drugs not only decreased PAP levels, but also systemic blood pressure.
Unlike systemic vasodilators, inhaled NO acts as a selective pulmonary vasodilator, acting primarily on the endothelium tissue of the lung. Upon inhalation, NO is absorbed into the capillary blood in the precapillary airspaces and alveolar capillaries. Inhaled NO has negligible action beyond the site of its uptake since NO is rapidly inactivated by the reaction with hemoglobin to form methemoglobin.
The use of inhaled NO for PPH patients was quickly followed by the use of inhaled NO for other respiratory diseases. For example, NO has been investigated for the treatment of patients with increased airway resistance as a result of emphysema, chronic bronchitis, asthma, adult respiratory distress syndrome (ARDS), and chronic obstructive pulmonary disease, (COPD). Still other respiratory diseases where NO inhalation therapy is thought to be beneficial include, by way of illustration and not by way of limitation: allograft lung transplantation, ischemia-reperfusion injury, congestive heart failure, septic shock, and high-altitude pulmonary edema.
While NO has shown promising preliminary results with respect to the treatment and prevention of the diseases mentioned above, delivery methods and devices must cope with certain problems inherent with gaseous NO delivery. First, exposure to high concentrations of NO is toxic. NO is toxic in high concentrations, especially over 1000 ppm. Even lower levels of NO can be harmful if the time exposure is relatively high. For example, the Occupational Safety and Health Administration (OSHA) has set exposure limits for NO in the workplace at 25 ppm time-weighted average for eight (8) hours. Typically, NO is administrated to patients in the concentration range of about 1 ppm to about 100 ppm.
Another problem with the delivery of NO is that NO rapidly oxidizes in the presence of oxygen to form NO2, which is highly toxic, even at low levels. For example, OSHA has set exposure limits for NO2 at 5 ppm. In any NO delivery device it is thus desirous to reduce, to the largest extent possible, the conversion of NO to NO2. The rate of oxidation of NO to NO2 is dependent on numerous factors, including the concentration of NO, the concentration of O2, and the time available for reaction. One problem with the inhalation of NO is that when NO is therapeutically inhaled, it is often mixed with high concentrations of O2. Consequently, this increases the conversion rate of NO to NO2. It is thus preferable to minimize the contact time between NO and O2 when the NO is combined with a source of oxygen gas.
Methods and devices for delivering NO to a patient have been developed to minimize the conversion of NO to NO2. For example, with respect to the delivery of NO to patients connected to a mechanical ventilator, the NO/NO2 stream has been introduced directly into the respiratory limb of a patient. See Martin Francoe, et al., “Inhaled Nitric Oxide: Technical Aspects of Administration and Monitoring,” Critical Care Medicine, Vol. 26, No. 4, pp. 785-87 April 1998. This arrangement has the advantage over other designs that combine and mix NO/NO2 and Air/O2 prior to their input to the ventilator since the contact time between NO and O2 is reduced.
Another delivery method and device that reduces the exposure to O2 and to a certain extent NO is disclosed in the U.S. Pat. No. 5,839,433 issued to Higenbottam. The '433 patent discloses a method and apparatus for supplying NO to a patient. According to the '433 patent, a very short pulse of NO is delivered intermittently, either at the start or end of inspiration. The '433 patent thus teaches the delivery of a bolus or plug of nitric oxide to the patient by administering a very short pulse of NO during inspiration. The timing of the delivery (beginning vs. late) is altered depending on the disease that is to be treated. When NO is desired in the lowermost depths of the lungs, for example, during treatment of pulmonary hypertension where NO acts on the small pulmonary arteries and capillaries, a short pulse is given at the beginning of inspiration. On the other hand, for asthma-like airway diseases, a very short pulse is administered near the end of inspiration. This method attempts to deliver NO to the desired location of the lungs. The method reduces the total exposure of the lungs to NO as well as reduces the total amount of NO available to react with O2 to form toxic NO2.
The pulses of NO delivered according to the '433 patent are of a predetermined width, which can be altered by changing the amount of time that a control valve is left open. The '433 patent, however, fails to disclose the proportional delivery of NO gas to the patient having a flow profile that tracks or is proportional or quasi-proportional to the flow profile of an oxygen-containing gas. Rather, the valve mechanism provides a bolus, or square wave-type “plug” of NO to the patient, the length of which, is altered by adjusting its width (i.e., holding the valve in the open position for a longer period of time). In this regard, the pulse has the flow profile of a square wave regardless of the profile of the patient's inspiration profile.
Generally, NO is administered to patients that are either spontaneously breathing or connected to a mechanical ventilator. In spontaneously breathing patients, a patient typically wears a tight fitting mask, transtracheal O2 catheter, nasal cannula, or other tubing passing directly into the airway of a patient. NO is typically mixed with O2 and air prior to introduction into the patient airway. See Dean Hess, Ph.D., et al., “Delivery Systems for Inhaled Nitric Oxide,” Respiratory Care Clinics of North America, Vol. 3, No. 3, pp. 402-404 September 1997. These spontaneous systems, however, suffer from the limitation that the NO concentration can fluctuate within a relatively wide range. The dose of NO varies with the patient's ventilatory pattern due to the fact that the patient's inspiration profile changes on a breath-by-breath basis. The delivered dose of NO is thus approximated from assumptions regarding the patient's ventilatory pattern.
There are several different methods of delivering NO to a mechanically-ventilated patient. In one method, the NO/N2 stream is premixed with Air/O2 prior to entering the ventilator. While such pre-mixing may better permit the inspired concentration of NO to be controlled, the production of NO2 is significantly higher given the longer contact time between NO and O2. This is particularly true for ventilators with large internal volumes.
In another method of delivery, NO is continuously injected into the inspiratory limb of the ventilator circuit. This method, however, has difficulty maintaining a stable NO concentration throughout the entire inspiration flow. Moreover, when continuously injected NO is used with adult ventilators that have phasic flow patterns (flow only during inspiration), the inspiratory circuit fills with NO during expiration, and a large bolus of NO is delivered to the patient in the next breath. See, e.g., Dean Hess, Ph.D., et al., “Delivery Systems for Inhaled Nitric Oxide,” Respiratory Care Clinics of North America, Vol. 3, No. 3, p. 381 September 1997. This method may result in an inspired NO concentration that may be more than double the calculated or estimated dose. In addition, the concentration of delivered NO varies with the length of the patient's expiration. For example, when the expiratory time is short, the delivered NO concentration is lower due to less time for filling the inspiratory limb with NO.
Yet another method of delivering NO involves intermittent injections of an NO-containing gas into the patient's inspiratory limb. In this regard, NO is delivered into the inspiratory limb only during the inspiratory phase. For this method to be acceptable, however, the flow from the ventilator must be continuously and precisely measured, and the injected does of NO must be precisely titrated such that the delivered NO and inspiratory flow waveform are not affected. See, Dean Hess, Ph.D., et al., “Delivery Systems for Inhaled Nitric Oxide,” Respiratory Care Clinics of North America, Vol. 3, No. 3, p. 384, September 1997.
One such commercial device operating on the above-mentioned intermittent injection principle is the I-NOvent Delivery System (Ohmeda). In the I-NOvent Delivery System a device separate and apart from the mechanical ventilator injects NO directly into the inspiration circuit of the patient. Flow in the inspiration limb of the circuit is measured via a flow sensor and NO is injected in proportion to the measured flow to provide the desired dose. See, Dean Hess, Ph.D., et al., “Delivery Systems for Inhaled Nitric Oxide,” Respiratory Care Clinics of North America, Vol. 3, No. 3, p. 395, September 1997.
Another commercial device utilizing intermittent injection of NO is the NOdomo device (Dragerwerk, Germany). The NOdomo device interfaces, like the I-NOvent Delivery System, with a separate mechanical ventilator. NO addition is controlled via a mass flow controller, adding a proportion of NO into the breathing circuit. Unlike the I-NOvent Delivery System, however, the NOdomo device controls NO flow delivery from an electronic flow controller that receives an input signal directly from the ventilator. See, Dean Hess, Ph.D., et al., “Delivery Systems for Inhaled Nitric Oxide,” Respiratory Care Clinics of North America, Vol. 3, No. 3, p. 399 September 1997.
U.S. Pat. No. 5,558,083 issued to Bathe et al. discloses a NO delivery system. The delivery system can be used with a mechanical ventilator as well as a gas proportioning device for spontaneous-breathing. A CPU controls a proportional control valve that is in-line with a source of NO gas. The CPU calculates the desired flow from, among other things, the flow of breathing gas measured via a flow sensor 46 and NO concentration measured by NO sensor 65. The proportional control valve 24 is controlled to arrive at the desired NO concentration.
In a second embodiment of the Bathe et al. device, a supplemental supply of O2 74 is connected to the NO line. A proportional control valve 78 is positioned in-line with the O2 supply 74 and reports to the CPU 56. As disclosed in the '083 patent, the O2 is provided as a safety measure should the O2 level fall below a critical level. Col. 8, lines 50-61. In the event that the level of O2 has dropped below the minimum threshold, the CPU 56 directs the proportional flow controller to increase the flow of O2 to the NO/N2 stream.
The '083 patent, however, fails to teach or suggest the proportional-type control of NO/N2, or O2 to track or match the flow of either O2 or the inspiration profile of a patient. Rather, the O2 is used as a safety measure should the O2 concentration fall below a threshold value. Moreover, in the devices disclosed in the '083 and '433 patents, residual NO gas is left in the device/inspiration limb between breaths.
It is thus desirous to have a device and method of delivery of NO to a patient that can control the delivery of an NO-containing gas as well as an oxygen-containing gas to a patient via a single controller. The device preferably can provide either a constant concentration of NO to the patient during inspiration or a non-constant concentration of NO to the patient depending on the desired setting. In addition, the device preferably does not suffer from the limitation of other delivery systems, where NO may remain in the system between breaths. Namely, the device and method preferably eliminates any bolus or residue of NO-containing gas that might build-up between breaths.
In addition to its effects on pulmonary vasculature, NO may also be introduced as a anti-microbial agent against pathogens via inhalation or by topical application. See e.g., WO 00/30659, U.S. Pat. No. 6,432,077, which are hereby incorporate by reference in their entirety. The application of gaseous nitric oxide to inhibit or kill pathogens is thought to be beneficial given the rise of numerous antibiotic resistant bacteria. For example, patients with pneumonia (often acquired through use of a ventilator, e.g., VAP) may not respond to antibiotics given the rise of antibiotic resistant strains associated with these conditions.
Clinical use of nitric oxide for inhalation has conventionally been limited to low concentration of nitric oxide given the potential toxicity. The toxicity may stem from binding of nitric oxide to hemoglobin that give rise methemoglobin or from the conversion of nitric oxide gas to nitrogen dioxide (NO2). However, to overwhelm pathogenic defense mechanisms to nitric oxide, it is desirable to deliver nitric oxide at a higher concentration (e.g., between 150 ppm to 250 ppm, and even to 400 ppm) than has traditionally been used clinically for inhalation. Thus, a need exists for a delivery method that is effective against combating pathogens and minimizing the risk of toxicity.